Hematopoietic Stem Cell Transplantation in the Elderly: More Questions Than Answers

Hematopoietic stem cell transplantation (HSCT) is an aggressive and expensive therapy formulated, in part, to achieve cure in patients with very high-risk or relapsed hematologic malignancies thought to be incurable with standard therapy.[1] Mortality rates have continued to improve with methodologic and supportive care advances, but these remain significant, particularly in the older adult. The procedure requires considerable pretransplant planning, multidisciplinary expertise, personal and cancer center resources, and intense follow-up care.

The Ballester/Tirona/Ballester article provides a systematic review of the data in elderly patients in an attempt to help us manage our older patients. The authors point out immediately, however, that data are generally insufficient to make firm clinical recommendations in an evidenced-based manner for HSCT in the elderly, adding an appropriate plea for increased trials to provide data that will improve our clinical decision-making.

Assessing Fitness for Therapy

Historically, patients selected for clinical trials based on established data-derived indications and protocols for the application of HSCT for hematologic malignancies have been restricted to patients less than 50 years old for allogeneic transplant and under 65 for autologous transplant. Use of a single chronologic age as a precise cutoff to indicate clinical fitness for therapies that produce a wide range of organ toxicities from chemotherapy, radiation, graft-vs-host disease, and other insults is well recognized to be problematic. When allogeneic transplant was first implemented, an age over 35 was too old. The development of nonmyeloablative and reduced-intensity conditioning allogeneic HSCT has expanded the age limit.

Since HSCT can be considered one of our most aggressive treatments, with significant morbidity and mortality, this is a clinical situation in need of accurate predictive methodologies for fitness rather than age. Approaches in general oncology practice are under development including applications such as the comprehensive geriatric assessment of fitness for older patients with cancer.[2-4] For HSCT, the authors review a general transplant fitness assessment tool that includes an analysis of comorbidities,[5] which recently has been applied to acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).[6] Overall, as reviewed by the authors and discussed below, such fitness measures in elderly adults need further development and application in the transplant arena.

Mobilizing Stem Cells

In the first part of their review, Ballester, Tirona, and Ballester consider three critical questions that are particularly relevant for the older patient. First, can the older individual mobilize sufficient numbers of hematopoietic stem cells that functionally restore stable and long-term hematopoiesis in the recipient? Anyone who has practiced hematology and evaluated bone marrow specimens from individuals of different ages is familiar with the predictable decreased cellularity seen with increasing age (10% per decade, on average). The reported decline in hematopoietic reserve, therefore, is not surprising.

The authors review interesting murine data showing that we have much to learn. Older mice are more anemic but can mobilize more hematopoietic stem cells and progenitor cells.[7,8] Additionally, myeloid/lymphoid ratios and stromal functions are abnormal, potentially of great significance in graft biology and the development of graft-vs-host disease. In healthy older humans, CD34+ peripheral blood stem cells are decreased, and again, myeloid/lymphoid ratios are altered, but not necessarily in the same direction as in mice.[9]

Interestingly, the response of hematopoietic stem cells to hematopoietic growth factors may differ in older individuals as well.[10] Although progress awaits the development of biologic measures of bone marrow reserve, advances in improved peripheral blood stem cell mobilization and expansion, and alternative graft sources including double cord transplants and embryonic stem cells, Ballester and coauthors identify studies that support the idea that older individuals—including those over 70—can mobilize sufficient numbers of hematopoietic stem cells to functionally restore stable and long-term hematopoiesis.